6-Lactam formation

Straightforward lactam formation has been used in a few instances. Thus 176 (R = H, R = NO2) with phosphorus oxychloride and... 

Reductive alkylation has been used to prepare a-amino acids suitable for lactam formation and further elaboration. In a single step a carbobenzyloxy group was removed, and alkylation with glyoxylic acid hydrate was achieved (18). 

In 1991, Ohfune and coworkers reported palladium(O)-catalyzed carbonylation of vinylaziridines 262 with carbon monoxide (1 atm.) in benzene (Scheme 2.65) [31]. Interestingly, 3,4-trans-azetidinone 264 was exclusively obtained from a dia-stereomeric mixture of trans- and cis-vinylaziridines 262 (3 1). Tanner and Somfai synthesized (+)-PS-5 (267) by use of palladium(O)-catalyzed trons-selective (3-lactam formation in the presence of Pd(dba)3 CHC13 (15mol%) and excess PPh3 in toluene. 

In analogy, Ugi et al. reported on a lactam formation by running a one-pot three components reaction the condensation of L-lysine 7, isobutyraldehyde and methyl isocyanide led to the corresponding a-amino-c-caprolactam 9, but the yield was not given. The authors presumed either a nucleophilic substitution of the ester 8 as the primary Ugi product by the amino function of the side chain or, alternatively, the nucleophilic attack of the NH2-group on an intermediately formed 0-acylamide and a subsequent rearrangement (Scheme 1) [4]. 

The effect of micelles in the pre-organization of acyclic compounds in a thir-teen-membered lactam formation using a modified Mukaiyama reagent was investigated by Rico [9]. 

Azolium enolates such as 65 can be generated directly through addition of NHCs to symmetrical or unsymmetrical ketenes. For example, Smith and co-workers have shown that NHC promoted p-lactam formation from isobutylphenylketene 61 and AT-tosyl imines 63 proceeds with good yields and moderate levels of diastereoselec-tivity via enolate 65 (Scheme 12.12) [17]. 

Scheme 12.57 Rationale for enantio- and diastereoselective P-lactam formation...

Entries 19 and 20 are examples of lactam formation by ring expansion of cyclic... 

It is interesting to note that some 1,5-benzodiazepines such as 29 also possess CNS depressant activity. Treatment of substituted diphenylamine 26 with methyl malonyl chloride and reduction with Raney nickel led to orthophenylenediamine analogue 27. Sodium alkoxide treatment led to lactam formation (28), and alkylation in the usual way with NaH and methyl iodide produced clobazam (29). °... 

Other quinoline A-oxide derivatives have been examined. A 1,3-oxazepine is the major product of irradiation of 2-cyanoquinoline A-oxide whereas lactam formation predominates on irradiation of 4-methylquinoline N-oxide in aqueous ethanol.60 Lactam formation has been shown to be influenced by an external magnetic field and on this basis it has been proposed that the first step in this transformation is the formation of an excited radical-ion pair.61 1,3-Oxazepines undergo further reaction on prolonged irradiation. The synthesis of 4-substituted indoles, for example, has been accomplished in this way by irradiation of 5-substituted quinoline A-oxides.62... 

Scheme 6.177 a-Methylenation of ketones [335], lactam formation from lactones [336], urea formation [337], and Knoevenagel condensation [338, 478]. 

Also, Bose et al. [76] have shown that the steric course of /J-lactam formation can be influenced by the MW heating rate. For example, in the reaction of the benzoylox-yacetyl chloride 53 with the Schiff base 54 (Scheme 4.28) the cis adduct 55 is the main product at low irradiation power whereas high power favors the formation of the trans adduct 56. Lactams of this type can serve as intermediates for the side chain oftaxol and its analogs. 

In 1991 Bose described the synthesis of ot-vinyl /1-lactams by reaction of ,/l-unsa-turated acyl chlorides with a Schiff base in chlorobenzene under microwave irradiation (an example of the eco-friendly MORE chemistry, in which only a limited amount of solvent is used) [20b]. Under these conditions, a-vinyl /1-lactam formation can be achieved in 65-70% in approximately 5 min (classical conditions require several hours and lead only to modest yields). 

To explain the formation of p-lactam formation two plausible mechanisms have been suggested (Scheme 2.320). 

Recently, Yu and co-workers developed an operationally simple catalytic system based on [RuCl2(/>-cymene)]2 for stereoselective cyclization of a-diazoacetamides by intramolecular carbenoid C-H insertion.192 /3-Lactams were produced in excellent yields and >99% m-stereoselectivity (Equation (53)). The Ru-catalyzed reactions can be performed without the need for slow addition of diazo compounds and inert atmosphere. With a-diazoanilide as a substrate, the carbenoid insertion was directed selectively to an aromatic C-H bond leading to y-lactam formation (Equation (54)). 

H. B. Hucker, S. C. Staufer, R. E. Rhodes, Metabolism of a Pharmacologically Active Pyrrolidine Derivative (Prolitane) by Lactam Formation , Experientia 1972,28, 430-431. 

Chapt. 5 is entirely devoted to the hydrolytic ring opening of lactams. The reverse reaction, namely lactam formation by cyclization-dehydration, has been seldom reported in the literature, suggesting that the reaction is, indeed, uncommon. However, it is also conceivable that lactam formation has sometimes been overlooked, and that much remains to be discovered regarding structural conditions for lactam formation, the factors that influence the lactam/amino acid equilibrium, and the role of enzymes. 

Lactam formation has been documented for a few drugs or drug metabolites. For example, the in vivo formation of a primary lactam metabolite was reported for bromfenac and perindopril. Bromfenac (11.144) is an anti-inflammatory agent, which, in humans and monkeys, is cyclized to the lactam 11.145, the first metabolite to appear in urine [159], At later times post-dose, hydroxylated and conjugated metabolites of 11.145 are excreted. Thus, cy-clization by dehydration appears to be the major if not the sole primary re-... 

The examples of bromfenac and perindopril clearly demonstrate that, given properly positioned amino and carboxylate groups, lactam formation is, indeed, a distinct metabolic possibility. 

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